DESCRIPTION: (Applicant's Abstract) The research program outlined herein is directed toward the design and development of general strategies for the syntheses of natural and unnatural products that exhibit significant biological activity. During the course of these investigations, the scope and limitations of selected reactions and processes will be explored in the context of the total synthesis of complex molecules, and new methods for carbon-carbon bond formation and functional group manipulation will be discovered and developed. The specific objectives include completing the total syntheses of several biologically important natural products including the macrolide antibiotic erythromycin B, the antifungal antibiotic ambruticin, the anticancer agent FR-900482, and the squalene synthase inhibitor and antifungal agent zaragozic acid A. The basic strategies for the syntheses of these compounds are unique and involve the stereoselective elaboration of furans and hydropyrans derived therefrom, asymmetric cyclopropanations, ring closing metatheses, and vinylogous aldol reactions. The approach to erythromycin B features a non-biogenetic macrolactonization of a fully glycosylated seco-acid derivative. New biologically active targets have been selected that will serve as the forum for the invention of novel chemistry. For example, a general strategy for the synthesis of C-aryl glycoside antibiotics will be developed that features (4+2) cycloadditions of substituted furans with benzynes followed by the opening of the oxabicycloheptene adducts thus produced with glycosyl anions. The utility of the approach will then be demonstrated by its application to the synthesis of the anticancer agent rubiflavin A as well as other representative C-aryl glycosides such as galtamycinone. Quantities of the natural products and selected congeners will be prepared for submission to C. P. Starks, Inc., Eli Lilly Company, Merck, Abbott Laboratories, Pfizer, and GlaxoWellcome for biological evaluation as potential antibiotics and as antifungal, hypocholesterolemic and anticancer agents.